Thiophene substituted antitumor antifolates

Abstract

A new thiophene substituted antitumor antifolate, N{[5-(2,4-diamino-6-pteridinyl)ethyl]2-theonyl}-L-glutamic acid having the structural formula 1 is provided, as well as methods for its preparation. The new thiophene substituted antifolate 1 is a very potent inhibitor of the enzyme dihydrofolate reductase, undergoes moderate polyglutamylation and is transported to tumor cells more effectively than methotrexate. Compound 1 is an excellent inhibitor of tumor cells growth in culture, the potency being superior to methotrexate against CCRF-CEM human lukemia cells.

Having regard to the foregoing disclosure, the following is claimed as inventive and patentable embodiments thereof: 
     
       1. N-{[5-(2,4-diamino-6-pteridinyl)ethyl]-2-theonyl}-L-glutamic acid having the following chemical structure: ##STR1## 
     
     
       2. A compound having the following structure where R 1  and R 2  are hydrogen and R 3  is a methyl or ethyl group ##STR2## 
     
     
       3. A pharmaceutical composition in dosage unit form for treating leukemia, ascites tumors or solid tumors comprising an amount within the range of about 0.1 to about 500 mg of N-{[5-(2,4-diamino-6-pteridinyl-ethyl]-2-theonyl}-L-glutamic acid per dosage unit therapeutically effective to ameliorate leukemia, ascites tumors or solid tumors together with a pharmaceutically acceptable nontoxic carrier or diluent thereof. 
     
     
       4. A process for treating leukemia, ascites tumors or solid tumors which comprises administrating orally or parenterally to a warm blooded animal having an abnormal proportion of leukocytes or other evidence of malignancy, a therapeutic and relatively non-toxic amount of N-{[5-(2,4-diamino-6-pteridinyl)ethyl]-2-theonyl}-L-glutamic acid (1) to ameliorate leukemia, ascites tumors or solid tumors.